FBXW7 suppresses epithelial-mesenchymal transition, stemness and metastatic potential of cholangiocarcinoma cells.
FBXW7 suppresses epithelial-mesenchymal transition, stemness and metastatic potential of cholangiocarcinoma cells.
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FBXW7 抑制胆管癌细胞的上皮间质转化、干性和转移潜能
DOI：
10.18632/oncotarget.3355
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发表时间：
2015-03-20
期刊：
影响因子：
--
通讯作者：
Chen Y
中科院分区：
文献类型：
--
作者：
Yang H;Lu X;Liu Z;Chen L;Xu Y;Wang Y;Wei G;Chen Y
上皮-间充质转化(EMT)在肿瘤转移中起着基础性作用。泛素连接酶FBXW7是一种常见的肿瘤抑制因子，参与多种细胞过程，但其在胆管细胞癌转移中的作用尚不清楚。在这里，我们报告了FBXW7通过调节EMT在CCA转移中的关键作用。在CCA细胞和临床标本中检测到FBXW7的表达缺失。临床病理分析显示，FBXW7缺乏与肝内CCA和肝门周围CCA的转移、TNM分期和分化程度密切相关。此外，FBXW7在CCA细胞中的沉默显著促进了EMT、干细胞样能力和体内、外转移。相反，FBXW7的过度表达减弱了这些过程。机制上，mTOR抑制剂雷帕霉素在体内和体外均能抑制FBXW7沉默所诱导的EMT、干细胞样能力和转移。此外，经雷帕霉素处理后，EMT调控转录因子Snail、Slug和ZEB1的表达也显著降低。此外，沉默ZEB1抑制了CCA细胞和FBXW7缺陷的CCA细胞的EMT和转移，提示ZEB1在FBXW7/mTOR信号通路相关的CCA转移中可能发挥作用。综上所述，我们的研究结果明确了FBXW7通过调节EMT在CCA转移中的关键作用。
Epithelial-mesenchymal transition (EMT) plays a fundamental role in cancer metastasis. The ubiquitin ligase FBXW7, a general tumor suppressor in human cancer, has been implicated in diverse cellular processes, however, its role in cholangiocarcinoma (CCA) metastasis has not been identified. Here, we report a crucial role of FBXW7 in CCA metastasis by regulating EMT. Loss of FBXW7 expression was detected in CCA cells and clinical specimens. Clinicopathological analysis revealed a close correlation between FBXW7 deficiency and metastasis, TNM stage and differentiation in intrahepatic CCA and perihilar CCA. Moreover, FBXW7 silencing in CCA cells dramatically promoted EMT, stem-like capacity and metastasis both in vitro and in vivo. Conversely, FBXW7 overexpression attenuated these processes. Mechanistically, treatment with rapamycin, a mTOR inhibitor, inhibited EMT, stem-like capacity and metastasis induced by FBXW7 silencing both in vitro and in vivo. Furthermore, the expression of EMT regulating transcription factors, snail, slug and ZEB1, were also decreased markedly with rapamycin treatment. In addition, silencing ZEB1 inhibited EMT and metastasis of both CCA cells and FBXW7 deficient CCA cells, which implicated the potential role of ZEB1 in FBXW7/mTOR signaling pathway related CCA metastasis. In conclusion, our findings defined a pivotal function of FBXW7 in CCA metastasis by regulating EMT.
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影响因子：
25.7
作者：
Claperon, Audrey;Mergey, Martine;Fouassier, Laura
通讯作者：
Fouassier, Laura
影响因子：
29.4
作者：
Lee, Mi-Jin;Yu, Gyung-Ran;Kim, Dae-Ghon
通讯作者：
Kim, Dae-Ghon
EMT，癌症干细胞和耐药性：癌症战争中新兴的邪恶轴。
影响因子：
8
作者：
Singh, A.;Settleman, J.
通讯作者：
Settleman, J.
胆管癌：发病机理，诊断和治疗的进展。
影响因子：
13.5
作者：
Blechacz, Boris;Gores, Gregory J.
通讯作者：
Gores, Gregory J.
影响因子：
--
作者：
Chen MH;Chiang KC;Cheng CT;Huang SC;Chen YY;Chen TW;Yeh TS;Jan YY;Wang HM;Weng JJ;Chang PM;Liu CY;Li CP;Chao Y;Chen MH;Huang CY;Yeh CN
通讯作者：
Yeh CN